Non-steroidal anti-inflammatory drugs (NSAID) having analgesic and anti-inflammatory properties have been widely administered orally in the treatment of mild to severe pain, particularly for rheumatoid arthritis and osteoarthritis patients. Tolerance or addiction to these drugs is not generally a problem with their continuous use in the treatment of pain or in the treatment of acute or chronic inflammatory states. However, these drugs generally have a higher potential for adverse side effects at the upper concentrations (limits) of their effective dose ranges. Therefore, it is important that such non-steroidal anti-inflammatory drugs be accurately measured and administered orally.
These non-steroidal anti-inflammatory drugs, e.g., ibuprofen and naproxen, have been widely prescribed by physicians. These drugs are in general tolerated well by most patients and provide an effective means for control of pain and inflammatory processes, particularly for the rheumatoid arthritis and osteoarthritis patients. However, these non-steroidal anti-inflammatory drugs impart a burning sensation, have a bitter taste and aftertaste, and/or have an adverse mouth feel when taken orally.
Therefore, in order to make wider use of them while substantially eliminating the bitter taste, aftertaste and adverse mouth feel and make these drugs more pleasant upon taking them orally, there has long been desired a way to insure delivery of these drugs in their desired concentrations while avoiding their extremely bitter taste, lingering aftertaste and adverse mouth feel effects referred to above connected with their ingestion orally, thereby encouraging patient compliance.
Various ways and delivery systems have been attempted in the prior art to accomplish these and other objectives.
One such system is described in co-pending application of Thomas C. Powell and Massimo M. Calanchi Serial No. 819,609, filed Jan. 9, 1992 and entitled "Microencapsulated Taste-Masked Water Insoluble NSAID Drug Materials". That application is directed to preparation of individual taste-masked, high payload, microcapsules by microencapsulation of water-insoluble NSAID drug materials in the substantial absence of microcapsule agglomerates. These taste-masked microcapsules contain a high payload, e.g., about 83+ wt. % of said NSAID drug material and can be formulated into chewable tablets and liquid aqueous suspensions for medicinal use. Cellulose acetate phthalate is the sole micro-encapsulating polymer wall material.
Another such system is described by J. R. Nixon et al in an article entitled "The In Vitro Evaluation of Gelatin Coacervate Microcapsules" appearing in J. Pharm. Pharmac, 1971, 23 Suppl. 147S-155S. This article describes the microencapsulation of sulfadiazine with gelatin using sodium sulphate as the coacervation agent. The free flowing microcapsular material was hardened with formalin, although other hardening agents such as glutaraldehyde and acrolein could be used as cross linking agents. In vitro dissolution studies were carried out.
U.S. Pat. No. 4,766,012, issued to Valenti, teaches the microencapsulation of ibuprofen and naproxen. The microencapsulation method employed by Valenti involves dissolving a coating agent in water by salification to form an aqueous solution, dispersing the medicament particles first in water, then in the solution of salified coating agent to form a suspension, and adding an acidifying agent to precipitate the coating agent onto the particles of medicament and recovering the microcapsules thus formed.
U.S. Pat. No. 4,460,563, issued to Massimo Calanchi, discloses the microencapsulation of ibuprofen with hydroxypropylmethylcellulose phthalate.
U.S. Pat. Nos. 4,835,186; 4,835,187; and 4,835,188 are directed to making taste-neutral (taste-masked) ibuprofen in dry powder form. U.S. Pat. Nos. 4,835,186 and U.S. Pat. No. 4,835,187 involve obtaining this taste-neutral ibuprofen in powder form by spray drying suspensions of colloidal silica in organic solvent solutions of ibuprofen and a cellulose material.
In U.S. Pat. No. 4,835,186, issued to Gerald L. Reuter et al, the organic solvent is a mixture of lower alkanol, e.g., isopropanol, and ethyl acetate, and the cellulose material is cellulose acetate phthalate. This product is stated to contain about 40% to 70% by weight ibuprofen, about 15% to 50% by weight of cellulose acetate phthalate and about 5% to 40% by weight colloidal silica.
In U.S. Pat. No. 4,835,187, issued to Gerald L. Reuter et al, the organic solvent is a lower alkanol, e.g., isopropanol, or contains at least 50% lower alkanol, and the cellulose material is ethyl cellulose, hydroxyethyl cellulose, or hydroxypropylmethyl cellulose, alone or in admixture. The lower alkanol solvent has a colloidal silica suspended therein. This product is stated to contain about 40% to 70% by weight ibuprofen, about 15% to 50% of a cellulose material selected from the group consisting of ethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose and admixtures thereof and about 5% to 40% by weight colloidal silica.
In U.S. Pat. No. 4,835,188, issued to Ying T. R. Ho et al, the taste-neutral powder form of ibuprofen is obtained by spray drying a dispersion of ibuprofen and ethyl cellulose in water having a plasticizer dissolved or suspended therein. This powder is stated to contain about 63% to 77% by weight ibuprofen, about 25% to 40% by weight ethyl cellulose and about 2% to 7% weight plasticizer.
An article by H. P. Merkle et al entitled "Preparation and In Vitro Evaluation of Cellulose Acetate Phthalate Coacervate Microcapsules", J. Pharm Science 62 pp. 1444-1448 (1973) describes the microencapsulation of phenacetin by coacervation of aqueous cellulose acetate phthalate using sodium sulfate as the coacervating agent. The article in column 1 on page 1444 refers to other literature describing coacervate encapsulation, a common preparation technique being either simple coacervation of gelatin with ethanol or sodium sulfate as dehydrating agents or complex coacervation of gelatin acacia mixtures. The statement is made by the authors that "Coacervation methods with pure gelatin and mixtures are rather complicated and difficult to control, particularly with regard to the hardening of the shells and the recovery of the microcapsules". In the last complete paragraph in column 1 on page 1448, the authors refer to other literature as showing an extremely rapid initial release from gelatin coacervate microcapsules.
The present invention provides a method of simultaneously encapsulating ibuprofen using both gelatin and cellulose acetate phthalate as the encapsulating material to give the microcapsules a dual coating, the gelatin portion of the coating providing high bioavailability of the ibuprofen core and the cellulose acetate phthalate providing the taste-masking effect. The gelatin in the dual coating serves to temper the well known delayed release properties of the cellulose acetate phthalate without interfering with its taste-masking function.